Differential kynurenine pathway metabolism in highly metastatic aggressive breast cancer subtypes: beyond
Benjamin Heng1, Ayse A Bilgin2, David B Lovejoy3
1Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia. benjamin.heng@mq.edu.au.
Background:
Immunotherapy has recently been proposed as a promising treatment to stop breast cancer (BrCa) progression and metastasis. However, there has been limited success in the treatment of BrCa with immune checkpoint inhibitors. This implies that BrCa tumors have other mechanisms to escape immune surveillance. While the kynurenine pathway (KP) is known to be a key player mediating tumor immune evasion and while there are several studies on the roles of the KP in cancer, little is known about KP involvement in BrCa.
Methods:
To understand how KP is regulated in BrCa, we examined the KP profile in BrCa cell lines and clinical samples (n = 1997) that represent major subtypes of BrCa (luminal, HER2-enriched, and triple-negative (TN)). We carried out qPCR, western blot/immunohistochemistry, and ultra-high pressure liquid chromatography on these samples to quantify the KP enzyme gene, protein, and activity, respectively.
Results:
We revealed that the KP is highly dysregulated in the HER2-enriched and TN BrCa subtype. Gene, protein expression, and KP metabolomic profiling have shown that the downstream KP enzymes KMO and KYNU are highly upregulated in the HER2-enriched and TN BrCa subtypes, leading to increased production of the potent immunosuppressive metabolites anthranilic acid (AA) and 3-hydroxylanthranilic acid (3HAA).
Conclusions:
Our findings suggest that KMO and KYNU inhibitors may represent new promising therapeutic targets for BrCa. We also showed that KP metabolite profiling can be used as an accurate biomarker for BrCa subtyping, as we successfully discriminated TN BrCa from other BrCa subtypes.
Insights
The kynurenine pathway (KP) is dysregulated in HER2-enriched and triple-negative breast cancer (BrCa), with increased immunosuppressive metabolites. KP enzyme inhibitors show therapeutic potential for BrCa.
Area of Science:
- Oncology
- Immunology
- Metabolomics
Background:
- Immunotherapy shows limited success in breast cancer (BrCa) treatment, suggesting alternative immune evasion mechanisms.
- The kynurenine pathway (KP) is implicated in tumor immune evasion, but its role in BrCa remains understudied.
Purpose of the Study:
- To investigate the regulation and role of the kynurenine pathway (KP) in different breast cancer (BrCa) subtypes.
- To identify potential therapeutic targets and biomarkers within the KP for BrCa.
Main Methods:
- Analysis of KP enzyme gene, protein, and activity in 1997 clinical BrCa samples representing luminal, HER2-enriched, and triple-negative (TN) subtypes.
- Utilized quantitative PCR (qPCR), western blot/immunohistochemistry, and ultra-high pressure liquid chromatography.
Main Results:
- The kynurenine pathway (KP) is significantly dysregulated in HER2-enriched and TN BrCa subtypes.
- Upregulation of downstream KP enzymes KMO and KYNU increases immunosuppressive metabolites anthranilic acid (AA) and 3-hydroxylanthranilic acid (3HAA).
Conclusions:
- Inhibitors targeting KMO and KYNU present potential new therapeutic strategies for BrCa.
- KP metabolite profiling accurately differentiates TN BrCa from other subtypes, serving as a potential biomarker.
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